tbuckley/cabot-search huggingface dataset:
Abstract 3492: The small GTPase ARF6 augments BRAFV600E-MAPK signaling in melanomagenesis
Authors: Junhua Wang, Aaron Rogers, Coulson Rich, Lise Sorensen, Sheri Holmen, Roger Wolff, Allie Grossmann
Journal: Cancer Research (2023)

Abstract ARF6 is a member of the Ras superfamily of small GTPases and has critical functions in endo-membrane trafficking pathways. We previously reported that ARF6 is aberrantly activated in metastatic melanoma and that activation of ARF6 stimulates WNT5A/beta-catenin and PI3K/AKT signaling to promote invasion and accelerate metastasis. Herein, we discovered an ARF6 activation signature in primary melanomas that is associated with inferior overall survival, supporting a novel role for ARF6 in early-stage progression. Conversely, melanocyte-specific deletion of Arf6 in Dct;TVA::BrafV600E;Cdkn2aNull murine melanoma significantly reduced tumorigenesis and progression, and improved survival. Importantly, bulk tumor transcriptome analysis showed reduced expression of ERK-induced genes in these BRAFV600E tumors. Likewise, immunofluorescent staining of tumor sections showed a significant reduction of cytoplasmic and nuclear p-ERK levels. Together these data demonstrate that loss of ARF6 reduces BRAFV600E-MAPK signaling output in vivo. This is a provocative finding because it implies that endomembrane trafficking has a major role in promoting BRAFV600E-driven tumorigenesis. More specifically, ARF6 may be critical for augmenting BRAFV600E signaling. Consistent with this hypothesis, expression of activated ARF6(ARF6Q67L) in our murine BRAFV600E melanoma cells was associated with upregulation of BRAFV600E, p-MEK, and p-ERK levels, detected by Reverse Phase Protein Array analysis. In addition, ARF6Q67L tumor cells showed an increase in anti-apoptotic proteins with a reciprocal decrease in pro-apoptotic proteins. Knockdown of Arf6 in BRAFV600E human melanoma cells significantly reduced proliferation and sensitized cells to vemurafenib-induced apoptosis. Overall, our data reveal that ARF6 augments MAPK signaling in BRAFV600E-driven tumorigenesis. Further work is needed to understand if ARF6 mediates endomembrane-dependent signaling of the BRAFV600E-MAPK pathway. Citation Format: Junhua Wang, Aaron Rogers, Coulson Rich, Lise Sorensen, Sheri Holmen, Roger Wolff, Allie Grossmann. The small GTPase ARF6 augments BRAFV600E-MAPK signaling in melanomagenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3492.
Abstract 3016: Cancers attributable to infectious agents in Italy
Authors: Giulia Collatuzzo, Paolo Boffetta
Journal: Cancer Research (2023)

Abstract Objectives: The burden of cancer attributable to known risk factors has never been estimated in Italy. This study aimed to provide an evidence-based, consistent assessment of the burden of infection-related cancer in Italy. Methods: We calculated the proportion of cancers attributable to infectious agents to estimate the burden of infection-related cancer incidence (2020) and mortality (2017). Data on prevalence of infection were mainly derived from cross-sectional surveys among representative sample of Italian population. Data on relative risk were mainly derived from meta-analysis and large-scale studies. Attributable fraction was calculated based on the counterfactual scenario of no exposure to infection. National registries were used to obtain on the number of cancer cases and deaths. Results: We estimated 7.6% of total cancer deaths occurred in Italy in 2017 were attributable to infections, with higher proportion in men (8.1%) than in women (6.9%). Corresponding figures for incidence in 2020 were 6.9%, 6.1% and 6.5%. Helicobacter pylori (Hp) was the first cause of infection-related cancer deaths, with 3.3% of all cancer deaths and 2.4% of cancer cases followed by Hepatitis C virus (HCV, 1.8% and 1,3%) and Hepatitis B virus (0,9% and 0,6%), Human Papillomavirus 0.6% and 1,0%), Epstein-Barr virus ( 0,3% of both deaths and cases), Human Immunodeficiency Virus (0,9% for both) and Human Herpes Virus- 8 (0,4% and 0,2%). Conclusions: The burden of cancer attributable to infections was higher in Italy than in other high-income countries in which similar studies were conducted, including the US, due to excess Hp and ACV. Most of the cancer burden related to infections in Italy is due to agents for which common therapies (Hp, HCV) or vaccination (HPV, HBV) are available. Screening prevention policies are needed to control these cancers, which are largely avoidable. Population attributable fraction (%) of cancer deaths in selected studies, by sex. Sex Italy United States United Kingdom France Men 8.1 3.4 3.1 3.1 Women 6.9 3.3 4.3 4.4 Citation Format: Giulia Collatuzzo, Paolo Boffetta. Cancers attributable to infectious agents in Italy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3016.
Abstract 4864: ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression
Authors: Wen Zhao, Danlei Yu, Yifan Zhai, Shi-Yong Sun
Journal: Cancer Research (2023)

Abstract The successful treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) with ALK tyrosine kinase inhibitors (ALK-TKIs) represents a promising targeted therapy. As a result, various ALK-TKIs have been rapidly developed, some of which were already approved while some are being tested in clinical trials. Death receptor 4 (DR4; also called TNFRSF10A or TRAIL-R1) is a cell surface protein, which is supposed to function as a pro-apoptotic protein that transduces TRAIL death signal to trigger apoptosis. Its expression is positively regulated by MEK/ERK signaling and thus can be downregulated by MEK/ERK inhibition. This study thus focused on determining the effects of AKL inhibition on DR4 expression and the underlying mechanisms. ALK-TKIs such as brigatinib and alectinib effectively and preferentially inhibited AKT/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. This was also true to DR4 downregulation, which occurred even at 2 h post treatment. These ALK-TKIs did not affect DR4 protein stability, rather potently decreased DR4 mRNA expression. In parallel, they promoted degradation and decreased the levels of Fra-1 and c-Jun, two critical components of AP-1, and suppressed AP-1 (Fra-1/c-Jun)-dependent transcription/expression of DR4. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation on elucidating the biological significance of DR4 downregulation in ALK-targeted cancer therapy. Citation Format: Wen Zhao, Danlei Yu, Yifan Zhai, Shi-Yong Sun. ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4864.
Abstract 1441: p27Kip1 is upregulated in UMSCV-4 cells corresponding to entering a state of quiescence when treated with clobetasol
Authors: Gianna Minnuto, Luke North, Mack Ogden, Kia Haering, Jani E. Lewis
Journal: Cancer Research (2023)

Abstract Quiescence, the temporary exit from the cell cycle, presents therapeutic challenges to cancer management since it allows evasion of chemotherapy and radiotherapy treatment. Essential to the study of quiescence in carcinogenesis is an established model system. Our studies have found that clobetasol treatment of the vulvar cancer cell line, UMSCV-4 causes these cells to enter a state of dormancy. Subsequent removal of the cells from clobetasol show a return to normal cell proliferation, even after dormancy for 3 months. p27Kip1 protein has been used as marker for entry into quiescence. Using both antibodies against p27Kip1 and transfection of a modified p27Kip1 containing plasmid into the UMSCV-4 cells we found that p27Kip1 is upregulated by addition of clobetasol, reflecting that quiescence is being activated in the treated UMSCV-4 cells. Cells that were incubated in clobetasol for three months and then removed from clobetasol (UMSCV-4 LT), allowing them to reenter the cell cycle, no longer expressed p27Kip1 upon re-exposure to clobetasol. This establishes the UMSCV-4 cells as a good model system for the study of clobetasol induced quiescence in vulvar squamous epithelial cells. The importance of this work is underscored by the observation that clobetasol is often used to treat a common inflammatory disease of the vulva known as vulvar lichen sclerosus (VLS) and up to 65% of vulvar carcinomas arise in the background of VLS. Citation Format: Gianna Minnuto, Luke North, Mack Ogden, Kia Haering, Jani E. Lewis. p27Kip1 is upregulated in UMSCV-4 cells corresponding to entering a state of quiescence when treated with clobetasol [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1441.
Abstract 2390: Claudin-4 probe identifies triple negative breast cancer using multispectral optoacoustic tomography
Authors: Laycee Parsons, William M. MacCuaig, Lacey R. McNally
Journal: Cancer Research (2023)

Abstract Background: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. The cancer is known for the lack of estrogen and her2 receptors. TNBC has a 5-year survival rate of 77% as for the other breast cancers averaging out at 93%. The CL-750 probes are made to identify the claudin-4 that is expressed in TNBC, making it easy to identify the cancer quickly so we can treat quickly. Methods: TNBC, aggressive pancreatic and kidney cancer cell lines were used to assess the expression of claudin-4 via western blot. Based upon the C-terminal fragment of Clostridium perfingens, we synthesized a 30 aa peptide. CL peptide was conjugated to amine reactive HiLite 750 nm fluorescent dye. The CL-750 probes were purified using dialysis to remove unattached dye. MDA-MB-468 (TNBC), MDA-MB-231 (TNBC), S2VP10 (pancreatic), and 293 (kidney) cells were incubated with CL-750 probes for 30 minutes and evaluated with near infrared-fluorescence using Odyssey imaging software. Using the treated cells were then scraped into agar tissue mimicking phantoms, the probes were assessed for optoacoustic activity using the MSOT (Multispectral optoacoustic tomography). Results: Using western blot to show expression of claudin-4 within cell lines the S2VP10 pancreatic (positive control) showed the most expression of claudin-4, while the 293 kidney cells showed a lesser amount. Both MDA-MB-468 and MDA-MB-231 TNBC cells showed the lowest amount of claudin-4 nonetheless both showed enough to continue with experiments. Cell line S2VP10 showed an extreme amount of binding to probe, while as the probe also bound to both smaller amount of claudin positive breast cancer cell line (MDA-MB-231) and larger amount of claudin breast cancer cell line (MDA-MB-468). Both CL-Short-750 and CL-Long-750 showed signal using MSOT. The CL-Long-750 showed 2x as much signal as CL-Short-750 making the Cl-long-750 probe more efficient in identifying claudin positive cell TNBC (p&amp;lt;0.05). Conclusion: Both CL-750-probes have the capability of identifying claudin-4 positive cell lines, but CL-Long-750 was more effective and had greater binding. Citation Format: Laycee Parsons, William M. MacCuaig, Lacey R. McNally. Claudin-4 probe identifies triple negative breast cancer using multispectral optoacoustic tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2390.
Abstract 4760: KDM4A promotes NEPC progression through regulation of MYC expression
Authors: Celia Sze Ling Mak, Ming Zhu, Xin Liang, Feng Wang, Anh G. Hoang, Xinzhi Song, Peter Shepherd, Derek Liang, Jessica Suh, Jiwon Park, Miao Zhang, Eric Metzger, Roland Schule, Abhinav K. Jain, Ellen Karasik, Barbara A. Foster, Min Gyu Lee, Paul Corn, Christopher J. Logothetis, Ana Aparicio, Nora Navone, Patricia Troncoso, Jianhua Zhang, Sue-Hwa Lin, Guocan Wang
Journal: Cancer Research (2023)

Abstract Despite advancements in treatment, prostate cancer (PCa) remains the second leading cause of death among men. Neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of PCa and lacks life-prolonging treatment. Here we identified histone lysine demethylase KDM4A as a driver in NEPC progression and an effective therapeutic target. KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to adenocarcinoma. Knockdown or knockout of KDM4A in NEPC cell lines suppressed cancer cell growth in vitro and in vivo. Importantly, the inactivation of Kdm4a in a genetically engineered mouse model of prostate cancer reduces tumor burden, reduces the incidence of NEPC, and prolongs overall survival. Mechanistically, KDM4A directly regulates the transcription of MYC, which is hyper-activated in human and mouse NEPC. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduces NEPC cell growth in vitro and in vivo. Taken together, we demonstrate that KDM4A promotes NEPC progression through regulation of MYC expression and targeting KDM4A can be an effective therapeutic strategy for NEPC. Citation Format: Celia Sze Ling Mak, Ming Zhu, Xin Liang, Feng Wang, Anh G. Hoang, Xinzhi Song, Peter Shepherd, Derek Liang, Jessica Suh, Jiwon Park, Miao Zhang, Eric Metzger, Roland Schule, Abhinav K. Jain, Ellen Karasik, Barbara A. Foster, Min Gyu Lee, Paul Corn, Christopher J. Logothetis, Ana Aparicio, Nora Navone, Patricia Troncoso, Jianhua Zhang, Sue-Hwa Lin, Guocan Wang. KDM4A promotes NEPC progression through regulation of MYC expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4760.
Abstract 3793: Regulation of miR-124 expression by promoter methylation in CRC and its relationship with KITENIN expression
Authors: So-Yeon Park, Rui Zhou, Chathurika D. B. Gamage, Sultan Pulat, Mücahit Varlı, Hangun Kim
Journal: Cancer Research (2023)

Abstract The mechanisms that regulate microRNA expression in cancer are not fully understood. However, recently reported data show that the epigenetic mechanism plays an important role in the regulation of microRNA expression. In in this study, we investigated the relationship between miR-124 promoter methylation and target genes in CRC. The expression of miR-124 was increased by Aza treatment and the expression of KITENIN was decreased in CRC cells. First, we examined the methylation status of miR-124 promoter in two normal cell lines and seven CRC cell lines using pyrosequencing assay. As a result, miR-124 promoter was hypermethylated in CRC cells and low in normal cells. Next, we evaluated the DNA methylation status for a miR-124 promoter in paired colorectal normal tissues and colorectal cancer tissues specimens from 10 patients. Overall, methylation of the miR-124 promoter was high in cancer among clinical tissues, and the expression of miR-124 was low in cancer tissues. The expression of the KITENIN was also higher in cancer tissues than in normal tissues. These results prove that DNA hypermethylation contributes to the transcriptional down-regulation of miR-124 in colon cancer, and that the epigenetic silencing of miR-124 in cancer cells modulate the activity of KITENIN. Our findings provide basic data that can be useful for clinical treatment of CRC patients through the mechanism of miR-124 regulation identified as a regulator of KITENIN. Citation Format: So-Yeon Park, Rui Zhou, Chathurika D. B. Gamage, Sultan Pulat, Mücahit Varlı, Hangun Kim. Regulation of miR-124 expression by promoter methylation in CRC and its relationship with KITENIN expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3793.
Abstract 3959: Novel spliced isoform of the proteasome subunit ADRM1/Rpn13 promotes hepatocellular carcinoma (HCC) development through selective degradation of tumor suppressor p53
Authors: Yanmei Sun, Mingjing Xu, Ho Lee Wan, Alissa M. Wong, Kelvin K. Ng, Nathalie Wong
Journal: Cancer Research (2023)

Abstract The Ubiquitin-Proteasome System (UPS) is the major pathway in eukaryotic cells that regulates intracellular protein degradation and turnover. Cumulative evidence has suggested that defects in the UPS machinery are involved in the pathogenesis of human diseases, including cancer. The proteasome-associated polyubiquitin receptor ADRM1 (also known as Rpn13) orchestrates the process of substrate recruitment with deubiquitination in the proteasome through its N-terminal ubiquitin-binding domain and C-terminal activation of deubiquitinating enzyme. Using long-read SMRT-seq to profile the RNA splicing landscape in hepatocellular carcinoma (HCC), we previously reported on an unannotated alternative spliced variant of ADRM1 in human hepatocellular carcinoma (HCC) (Hepatology 2019). This novel isoform exhibits an exon 9 skipping (ADRM1-ΔEx9) that resulted in an altered C-terminus of the protein. In this study, we undertook further investigations to characterize the detailed functional effects of ADRM1-ΔEx9 in HCC biology and the underlying mechanism. Initial study by junction-specific Taqman PCR assay showed that ADRM1-ΔEx9 is more frequently upregulated in HCC tumors than the canonical full-length counterpart (ADRM1-FL). There is an interchange between the two isoforms as tumor develops which underscores an isoform-switch in favor of HCC development. Indeed, our result showed that ADRM1-ΔEx9, but not ADRM1-FL, correlated significantly with inferior patient survival. Functionally, ADRM1-ΔEx9 knockdown profoundly suppressed proliferation by inducing spontaneous apoptosis in HCC cell lines and patient-derived HCC organoids. The corresponding effects were less apparent from ADRM1-FL knockdown. Consistently, overexpression of ADRM1-ΔEx9 in normal human liver organoids promoted pre-malignant features alongside increased in-vitro propagation time. Ubiquitin Proteome profiling revealed that ADRM1-ΔEx9 led to a reduced expression of the pivotal tumor suppressor p53. A parallel transcriptome also substantiated that ADRM1-ΔEx9 modulated genes involved in the p53 and apoptosis pathways. Collectively, our study demonstrated that the non-canonical spliced isoform ADRM1-ΔEx9 confers growth and pro-survival advantages in HCC through mediating selective degradation of tumor suppressor p53 protein. Citation Format: Yanmei Sun, Mingjing Xu, Ho Lee Wan, Alissa M. Wong, Kelvin K. Ng, Nathalie Wong. Novel spliced isoform of the proteasome subunit ADRM1/Rpn13 promotes hepatocellular carcinoma (HCC) development through selective degradation of tumor suppressor p53. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3959.
Abstract 2871: Spatial landscape of the tumor microenvironment in pancreatic ductal adenocarcinoma using multiplexed imaging and AI based analysis
Authors: Michael J. Smith, Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, Katie O. White, Richard A. Heil-Chapdelaine, Melinda Angus-Hill
Journal: Cancer Research (2023)

Abstract Pancreatic tumors are highly heterogenous, often with more aggressive regions that are responsible for invasion and metastasis. These aggressive pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial to mesenchymal transition and create subregions in the tumor that evade treatments and provide a critical support niche for continued tumor growth and metastasis. Conventional chemotherapy plus radiation, or in advanced disease chemotherapy plus targeted drug therapy can lengthen patient survival. However, even in patients with local disease, the 5-year survival rate remains at around 40%, demonstrating that there is need for improved conventional and immune therapies for all pancreatic cancer patients. In this study, dozens of biomarkers have been used to probe tumor heterogeneity in pancreatic ductal adenocarcinoma (PDAC) tissue. We rely on the published finding that hypoxia gene expression is consistent in PDAC, regardless of tumor location, whether primary tumor or metastasis. With the spatial biology solution, Cell DIVETM and proprietary Spatial AI analytics software, dozens of biomarkers can be used to computationally reduce tumor heterogeneity, and to spatially define cells in the microenvironment within hypoxic and normoxic regions of PDAC, and in normal pancreas. We found that these hypoxic PDAC regions are devoid of immune cells in general, with the appearance of spatially co-localized populations of cell types consistent with tumor desmoplasia and inflammation. Taken together, multiplexed whole slide imaging and analysis enables spatially resolved whole tissue analysis of the tumor microenvironment, including new insights into spatial biology in the hypoxic PDAC environment. Citation Format: Michael J. Smith, Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, Katie O. White, Richard A. Heil-Chapdelaine, Melinda Angus-Hill. Spatial landscape of the tumor microenvironment in pancreatic ductal adenocarcinoma using multiplexed imaging and AI based analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2871.